Substituted tolyl esters of PGE1

ABSTRACT

Substituted phenyl and naphthyl esters of PGE 1 , 15-alkyl-PGE 1 , and 15(R)-15-alkyl-PGE 1 , and their racemic forms, and processes for producing them are disclosed. The products are useful for the same pharmacological and medical purposes as PGE 1 , 15-alkyl-PGE 1 , and 15(R)-15-alkyl-PGE 1 , and are also useful as a means for obtaining highly purified PGE 1 , 15-alkyl-PGE 1 , and 15(R)-alkyl-PGE 1  products.

This is a division of application Ser. No. 431,599, filed Jan. 8, 1974.

BACKGROUND OF THE INVENTION

This invention relates to novel ester derivatives of prostaglandin E₁(hereinafter identified as "PGE₁ "), 15-alkyl-PGE₁, 15(R)-15-alkyl-PGE₁, and their racemic forms, and to processes forproducing them.

PGE₁ is represented by the formula: ##SPC1##

A systematic name for PGE₁ is 7-{3α-hydroxy-2β-[(3S)-3-hydroxytrans-1-octenyl] -5-oxo-1α-cyclopentyl} -heptanoic acid. PGE₁ is knownto be useful for a variety of pharmacological and medical purposes, forexample labor induction and abortion in pregnant animals, includinghumans, menstrual regulation in both pregnant and non-pregnant animals,including humans, reduction and control of gastric secretion, and as ahypotensive agent to reduce blood pressure in mammals, including humans.See Bergstrom et al., Pharmacol. Rev. 20, 1 (1968) and references citedtherein. As to racemic PGE₁, see for example W. P. Schneider et al., J.Am. Chem. Soc. 91, 5372 (1969).

The 15-alkyl-PGE.sub. 1 analog and its 15(R) epimer are represented bythe formula: ##SPC2##

Wherein Y' is ##EQU1## following the usual convention wherein brokenline attachment of hydroxy to the side chain at carbon 15 indicates thenatural or "S" configuration and solid line attachment of hydroxyindicates the epi or "R" configuration. See for example Nugteren et al.,Nature 212, 38 (1966) and Cahn, J. Chem. Ed. 41, 116 (1964). The15-alkyl-and 15(R)-15-alkyl-PGE₁ analogs in their optically active andracemic forms are known. See for example U.S. Pat. No. 3,728,382. Theseanalogs are also useful for the above-described pharmacologicalpurposes.

Esters of the above compounds are known, wherein the hydrogen atom ofthe carboxyl group is replaced by a hydrocarbyl or substitutedhydrocarbyl group. Among these are the methyl ester of PGE₁ (B.Samuelsson, J. Biol. Chem. 238, 3229 (1963)), (see also U.S. Pat. No.3,069,322), the methyl esters of 15-methyl-PGE₁ and dl-15-methyl-PGE₁(G. L. Bundy et al., Ann. N.Y. Acad. Sci. 180, 76 (1971)), the ethylester of PGE₁ (R. Ryhage et al., Biochem. Biophys. Res. Commun. 19, 279(1965)), and the octafluoro-1-pentyl ester of PGE₁ (Belgian Pat. No.775,106, Derwent Farmdoc No. 33705T).

SUMMARY OF THE INVENTION

It is a purpose of this invention to provide novel ester derivatives ofprostaglandin PGE₁, 15-alkyl-PGE₁, 15(R)- 15-alkyl-PGE₁, and theirracemic forms. It is a further purpose to provide such esters derivedfrom substituted phenols and naphthols. It is a further purpose toprovide such esters in a free-flowing crystalline form. It is still afurther purpose to provide novel processes for preparing these esters.

The presently described esters include compounds represented by thegeneric formula: ##SPC3##

wherein Z is the substituted phenyl or naphthyl group as definedimmediately below, and Y is ##EQU2## i.e. esters of PGE₁,15-methyl-PGE₁, and 15(R)-15-methyl-PGE₁, 15-ethyl-PGE₁, and15(R)-15-ethyl-PGE₁, and also the racemic compounds represented by eachrespective formula and the mirror image thereof: Z being represented by##SPC4##

For example, PGE₁, p-acetamidophenyl ester, is represented by formulaIII when Y is ##EQU3## and Z is A, i.e. ##SPC5##

and is conveniently identified herein as the PGE₁ ester of formulaIII-A. Racemic compounds are designated by the prefix "racemic" or "dl";when that prefix is absent, the intent is to designate an opticallyactive compound. Racemic 15-methyl-PGE₁, p-benzamidophenyl ester,corresponds to formula III wherein Y is ##EQU4## and Z is B, i.e.##SPC6##

including of course not only the optically active isomer represented byformula III but also its mirror image.

The novel formula-III compounds and corresponding racemic compounds ofthis invention are each useful for the same purposes as described abovefor PGE₁ and are used for those purposes in the same manner known in theart, including oral, sublingual, buccal, rectal, intravaginal,intrauterine, or topical administration.

For many applications these novel prostaglandin esters which I haveobtained from certain specified phenols and naphthols have advantagesover the corresponding known prostaglandin compounds. Thus, thesesubstituted phenyl and naphthyl esters are surprisingly stable compoundshaving outstanding shelf-life and thermal stability. In contrast to theacid form of these prostaglandins, these esters are not subject toacid-catalyzed decomposition either by elimination of water or byepimerization. Thus these compounds have improved stability either insolid, liquid, or solution form. In oral administration these estershave shown surprisingly greater efficacy than the corresponding freeacids or lower alkyl esters, whether because of longer duration ofbiological activity or because of improved lipophilicity and absorptionis not certain. These esters offer a further advantage in that they havelow solubility in water and the body fluids and are therefore retainedlonger at the site of administration.

A particularly outstanding advantage of many of these substituted phenyland naphthyl esters is that they are obtained in free-flowingcrystalline form, generally of moderately high melting point, in therange 90°-180° C. This form is especially desirable for ease ofhandling, administering, and purifying. These crystals are highlystable, for example showing practically no decomposition at acceleratedstorage tests at 65° C., in comparison with liquid alkyl esters or thefree acids. This quality is advantageous because the compound does notlose its potency and does not become contaminated with decompositionproducts.

These crystalline esters also provide a means of purifying PGE₁,15-methyl-PGE₁, 15(R)-15-methyl-PGE₁, 15-ethyl-PGE₁, or15(R)-15-ethyl-PGE₁, which are first converted to one of these esters,recrystalized until pure, and then recovered as the free acid. Onemethod of recovering the free acid is by enzymatic hydrolysis of theester, for example with a lipase. See German Pat. No. 2,242,792, DerwentFarmdoc No. 23047U.

To obtain the optimum combination of stability, duration of biologicalactivity, lipophilicity, solubility, and crystallinity, certaincompounds within the scope of formula III are preferred.

One preference is that Z is limited to either ##SPC7##

Another preference is that Z is further limited to ##SPC8##

wherein R₁ is

    --CH.sub.3 ##SPC9##

    --NH.sub.2 ##SPC10## ##SPC11##

wherein R₂ is

    --CH.sub.3 ##SPC12##

    --NH.sub.2.

Another preference is that Z is limited to ##SPC13##

Another preference is that Z is limited to ##SPC14##

wherein R₃ is

    --CH.sub.3 ##SPC15##

    --NH.sub.2 ##SPC16##

    O--CH.sub.3 ;

or ##SPC17##

wherein R₄ is ##SPC18##

Especially preferred are those compounds which are in free-flowingcrystalline form, for example:

p-acetamidophenyl ester of PGE₁ or

p-benzamidophenyl ester of PGE₁.

The substituted phenyl and naphthyl esters of PGE₁, 15-alkyl-PGE₁, and15(R)-15-alkyl-PGE₁ encompassed by formula III wherein Z is defined byester groups A through Y are produced by the reactions and proceduresdescribed and exemplified hereinafter. For convenience, the aboveprostaglandin or prostaglandin analog is referred to as "the PGcompound". The term "phenol" is used in a generic sense, including bothphenols and naphthols.

Various methods are available for preparing these esters, differing asto yield and purity of product. Thus, by one method, the PG compound isconverted to a tertiary amine salt, reacted with pivaloyl halide to givethe mixed acid anhydride and then reacted with the phenol. Alternately,instead of pivaloyl halide, an alkyl or phenylsulfonyl halide is used,such as p-toluenesulfonyl chloride. See for example Belgian Pat. Nos.775,106 and 776,294, Derwent Farmdoc Nos. 33705T and 39011T.

Still another method is by the use of the coupling reagent,dicyclohexylcarbodiimide. See Fieser et al., "Reagents for OrganicSynthesis," pp. 231-236, John Wiley and Sons, Inc., New York (1967). ThePG compound is contacted with one to ten molar equivalents of the phenolin the presence of 2-10 molar equivalents of dicyclohexylcarbodiimide inpyridine as a solvent.

The preferred novel process for the preparation of these esters,however, comprises the steps (1) forming a mixed anhydride with the PGcompound and isobutylchloroformate in the presence of a tertiary amineand (2) reacting the (2) with an appropriate phenol or naphthol.

The mixed anhydride is represented by the formula: ##SPC19##

for the optically active PG compounds, Y having the same definition asabove.

The anhydride is formed readily at temperatures in the range -40° to-60° C., preferably at -10° to +10° C. so that the rate is reasonablyfast and yet side reactions are minimized. The isobutylchloroformatereagent is preferably used in excess, for example 1.2 molar equivalentsup to 4.0 per mole of the PG compound. The reaction is preferably donein a solvent and for this purpose acetone is preferred, although otherrelatively non-polar solvents are used such as acetonitrile,dichloromethane, and chloroform. The reaction is run in the presence ofa tertiary amine, for example triethylamine, and the co-formed aminehydrochloride usually crystallizes out, but need not be removed for thenext step.

The anhydride is usually not isolated but is reacted directly insolution with the phenol, preferably in the presence of a tertiary aminesuch as pyridine.

The phenol is preferably used in equivalent amounts or in excess toinsure that all of the mixed anhydride is converted to ester. Excessphenol is separated from the product by methods described herein orknown in the art, for example by crystallization. The tertiary amine isnot only a basic catalyst for the esterification but also a convenientsolvent. Other examples of tertiary amines useful for this purposeinclude N-methylmorpholine, triethylamine, diisopropylethylamine, anddimethylaniline. Although they may be used, 2-methylpyridine andquinoline result in a slow reaction. A highly hindered amine such as2,6-dimethyllutidine is not useful because of the slowness of thereaction.

The reaction with the anhydride proceeds smoothly at room temperature(about 20° to 30° C.) and can be followed in the conventional mannerwith thin layer chromatography (TLC), usually being found completewithin 1-4 hours.

The reaction mixture is worked up to yield the ester following methodsknown in the art, and the product is purified, for example by silica gelchromatography.

Solid esters are converted to a free-flowing crystalline form oncrystallization from a variety of solvents, including ethyl acetate,tetrahydrofuran, methanol, and acetone, by cooling or evaporating asaturated solution of the ester in the solvent or by adding a misciblenonsolvent such as diethyl ether, hexane, or water. The crystals arethen collected by conventional techniques, e.g. filtration orcentrifugation, washed with a small amount of solvent, and dried underreduced pressure. They may also be dried in a current of warm nitrogenor argon, or by warming to about 75° C. Although the crystals arenormally pure enough for many applications, they may be recrystallizedby the same general techniques to achieve improved purity after eachrecrystallization.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The invention can be more fully understood by the following examples.

All temperatures are in degrees centigrade.

Silica gel chromatography, as used herein, is understood to includechromatography on a column packed with silica gel, elution, collectionof fractions, and combination of those fractions shown by thin layerchromatography (TLC) to contain the desired product free of startingmaterial and impurities. "TLC," herein, refers to thin layerchromatography.

PREPARATION 1 p-Benzamidophenol

A solution of p-hydroxyaniline (20 g.) in 200 ml. pyridine is treatedwith benzoic anhydride (20 g.). After 4 hr. at about 25° C., the mixtureis concentrated under reduced pressure and the residue is taken up in200 ml. of hot methanol and reprecipitated with 300 ml. of water. Theproduct is recrystallized from hot acetonitrile as white crystals, 8.5g., m.p. 218.0°-218.5° C.

PREPARATION 2 p-(p-Acetamidobenzamido) phenol

A solution of p-acetamidobenzoic acid (12.5 g.) in 250 ml. oftetrahydrofuran is treated with triethylamine (11.1 ml.). The mixture isthen treated with isobutylchloroformate (10.4 ml.) and, after 5 min. atabout 25° C., with p-aminophenol (13.3 g.) in 80 ml. of dry pyridine.After 40 min. the crude product is obtained by addition of 2 liters ofwater. The product is recrystallized from 500 ml. of hot methanol bydilution with 300 ml. of water as white crystals, 5.9 g., m.p.275.0°-277.0° C.

EXAMPLE 1 p-Acetamidophenyl Ester of PGE₁ (Formula III-A).

A solution of PGE₁ (0.450 g.) and triethylamine (0.214 ml.) in 20 ml. ofacetone is treated at -20° C. with isobutylchloroformate (0.20 ml.)whereupon triethylamine hydrochloride is precipitated. After 5 min. themixture is treated with p-acetamidophenol (0.260 g.) in 10 ml. ofpyridine for 2 hr. at about 25° C. The solvent is removed under reducedpressure and the residue is dissolved in ethyl acetate and washed withwater. The organic phase is dried over sodium sulfate, concentrated, andsubjected to silica gel chromatography, eluting with ethyl acetatefollowed by acetonitrile. The residue obtained by concentration ofselected fractions, a solid on chilling, is the title compound, 0.600g., having R_(f) 0.3 (TLC on silica gel in ethyl acetate-acetic acid,97:3). It is recrystallized from ethyl acetate-hexane as whitefree-flowing crystals, m.p. 133.8°-136.3° C.

EXAMPLE 2 p-Benzamidophenyl Ester of PGE₁ (Formula III-B).

Following the procedure of Example 1 but using 0.490 g. of PGE₁, 0.230ml. of triethylamine, 0.216 ml. of isobutylchloroformate, and 0.400 g.of p-benzamidophenol there is obtained a crude solid residue. Thisresidue is subjected to silica gel chromatography, eluting with ethylacetate, then ethyl acetate-acetonitrile (1:1), and finallyacetonitrile. The residue obtained by concentration of selectedfractions, 0.496 g., is crystallized from acetone diluted with 1.5volumes of hexane as the title compound, 0.356 g., white free-flowingcrystals, m.p. 150.8°-154.8° C., having R_(f) 0.6 (TLC on silica gel inethyl acetate).

Following the procedures of Examples 1-2 but employing the racemic formsof the PG compounds, there are obtained the corresponding esters ofracemic PG compounds.

EXAMPLES 3-75

The substituted phenyl and naphthyl esters of PGE₁, 15-methyl-PGE₁, and15(R)-15-methyl-PGE₁ of Tables I-III below are obtained following theprocedures of Example 1, wherein the prostaglandin compound is reactedin the presence of triethylamine and isobutylchloroformate with theappropriate hydroxy phenyl or naphthyl compound, listed in the Table.These phenols or naphthols are readily available or prepared by methodsdescribed herein or known in the art. The crude products, obtained byconcentration under reduced pressure, are purified by means describedherein or known in the art, including partitioning, solvent extraction,washing, silica gel chromatography, trituration, or crystallization.

Following the procedures of Examples 3-75 but employing the racemicforms of the PG compounds, there are obtained the corresponding estersof the racemic PG compounds.

                  TABLE I                                                         ______________________________________                                        Esters of PGE.sub.1                                                                Hydroxy Phenyl or       Product PGE.sub.1                                Ex.  Naphthyl Compound       ester of formula:                                ______________________________________                                         3   p-(acetamidobenzamido)phenol                                                                          III-C                                             4   p-(p-benzamidobenzamido)phenol                                                                        III-D                                             5   p-hydroxyphenylurea     III-E                                             6   p-hydroxy-1,3-diphenylurea                                                                            III-F                                             7   p-phenylphenol          III-G                                             8   p-tritylphenol          III-H                                             9   N-acetyl-L-tyrosinamide III-I                                            10   N-benzoyl-L-tyrosinamide                                                                              III-J                                            11   p-hydroxybenzaldehyde   III-K                                                 semicarbazone                                                            12   p-hydroxyacetophenone   III-L                                            13   p-hydroxybenzophenone   III-M                                            14   p-hydroxybenzamide      III-N                                            15   o-hydroxybenzamide      III-O                                            16   N-(p-tritylphenyl)-P-   III-P                                                  hydroxybenzamide                                                        17   p-hydroxybenzoic acid,  III-Q                                                  methyl ester                                                            18   hydroquinone benzoate   III-R                                            19   hydroquinone, p-acetamido-                                                                            III-S                                                  benzoic acid ester                                                      20   2,4-diacetamidophenol   III-T                                            21   1-acetamido-4-hydroxy-  III-U                                                  napththalene                                                            22   1-benzamido-4-hydroxy-naphthalene                                                                     III-V                                            23   1-hydroxy-4-ureido-naphthalene                                                                        III-W                                            24   1-naphthol              III-X                                            25   1-hydroxy-5-naphthalene-sulfonamide                                                                   III-Y                                            ______________________________________                                    

                  TABLE II                                                        ______________________________________                                        Esters of 15-Methyl-PGE.sub.1                                                                             Product                                                Hydroxy Phenyl or      15-Methyl-PGE.sub.1                               Ex.  Naphthyl Compound      Ester of formula:                                 ______________________________________                                        26   p-acetamidophenol      III-A                                             27   p-benzamidophenol      III-B                                             28   p-(p-acetamidobenzamido)phenol                                                                       III-C                                             29   p-(p-benzamidobenzamido)phenol                                                                       III-D                                             30   p-hydroxyphenylurea    III-E                                             31   p-hydroxy-1,3-diphenylurea                                                                           III-F                                             32   p-phenylphenol         III-G                                             33   p-tritylphenol         III-H                                             34   N-acetyl-L-tyrosinamide                                                                              III-I                                             35   N-benzoyl-L-tyrosinamide                                                                             III-J                                             36   p-hydroxybenzaldehyde semicarbazone                                                                  III-K                                             37   p-hydroxyacetophenone  III-L                                             38   p-hydroxybenzophenone  III-M                                             39   p-hydroxybenzamide     III-N                                             40   o-hydroxybenzamide     III-O                                             41   N-(p-tritylphenyl)-p-hydroxybenzamide III-P                              42   p-hydroxybenzoic acid, methyl ester                                                                  III-Q                                             43   hydroquinone benzoate  III-R                                             44   hydroquinone, p-acetamido-                                                                           III-S                                                   benzoic acid ester                                                      45   2,4-diacetamidophenol  III-T                                             46   1-acetamido-4-hydroxynaphthalene                                                                     III-U                                             47   1-benzamido-4-hydroxynaphthalene                                                                     III-V                                             48   1-hydroxy-4-ureidonaphthalene                                                                        III-W                                             49   2-naphthol             III-X                                             50   1-hydroxy-5-naphthalene-                                                                             III-Y                                                   sulfonamide                                                             ______________________________________                                    

                  TABLE III                                                       ______________________________________                                        Esters of 15(R)-15-Methyl-PGE.sub.1                                                                       Product 15(R)-                                         Hydroxy Phenyl or      15-Methyl-PGE.sub.1                               Ex.  Naphthyl Compound      Ester of formula:                                 ______________________________________                                        51   p-acetamidophenol      III-A                                             52   p-benzamidophenol      III-B                                             53   p-(p-acetamidobenzamide)phenol                                                                       III-C                                             54   p-(p-benzamidobenzamido)phenol                                                                       III-D                                             55   p-hydroxyphenylurea    III-E                                             56   p-hydroxy-1,3-diphenylurea                                                                           III-F                                             57   p-phenylphenol         III-G                                             58   p-tritylphenol         III-H                                             59   N-acetyl-L-tyrosinamide                                                                              III-I                                             60   N-benzoyl-L-tyrosinamide                                                                             III-J                                             61   p-hydroxybenzaldehyde semicarbazone                                                                  III-K                                             62   p-hydroxyacetophenone  III-L                                             63   p-hydroxybenzophenone  III-M                                             64   p-hydroxybenzamide     III-N                                             65   o-hydroxybenzamide     III-O                                             66   N-(p-tritylphenyl)-p-hydroxybenzamide                                                                III-P                                             67   p-hydroxybenzoic acid, methyl ester                                                                  III-Q                                             68   hydroquinone benzoate  III-R                                             69   hydroquinone, p-acetamido-                                                                           III-S                                                   benzoic acid ester                                                      70   2,4-diacetamidophenol  III-T                                             71   1-acetamido-4-hydroxynaphthalene                                                                     III-U                                             72   1-benzamido-4-hydroxynaphthalene                                                                     III-V                                             73   1-hydroxy-4-ureidonaphthalene                                                                        III-W                                             74   2-naphthol             III-X                                             75   1-hydroxy-5-naphthalenesulfonamide                                                                   III-Y                                             ______________________________________                                    

I claim:
 1. An optically active compound of the formula: ##SPC20##or aracemic compound of that formula and the mirror image thereof, wherein Zis ##SPC21## and wherein Y is ##EQU5##
 2. The ester ofN-acetyl-L-tyrosinamide and PGE₁, a compound according to claim
 1. 3.The ester of N-benzoyl-L-tyrosinamide and PGE₁, a compound according toclaim
 1. 4. The ester of p-hydroxybenzaldehyde semicarbazone and PGE₁, acompound according to claim
 1. 5. The ester of N-acetyl-L-tyrosinamideand 15-methyl-PGE₁, a compound according to claim
 1. 6. The ester ofN-benzoyl-L-tyrosinamide and 15-methyl-PGE₁, a compound according toclaim
 1. 7. The ester of p-hydroxybenzaldehyde semicarbazone and15-methyl-PGE₁, a compound according to claim
 1. 8. The ester ofN-acetyl-L-tyrosinamide and 15(R)-15-methyl-PGE₁, a compound accordingto claim
 1. 9. The ester of N-benzoyl-L-tyrosinamide and15(R)-15-methyl-PGE₁, a compound according to claim
 1. 10. The ester ofp-hydroxybenzaldehyde semicarbazone and 15(R)-15-methyl-PGE₁, a compoundaccording to claim 1.